Plasmodium infection exacts a significant toll on human public health. More than 3.3 billion people are at risk for exposure and >250 million new cases of malaria are reported each year. Much effort has been directed towards developing immunologic strategies that target the clinically relevant blood stage of Plasmodium infection, but to date no licensed vaccines exist. In rodent models of Plasmodium blood stage infection, parasite-specific CD4 T cells have been shown to be necessary for protection. In humans, the presence of parasite-specific CD4 T cells correlates with resistance to severe disease. Importantly, the precise characteristics of protective CD4 T cell responses (numbers, phenotype, functional attributes) remain largely unknown. The candidate has recently developed and applied a novel surrogate activation marker approach to track the total, parasite-specific CD4 T cell response during Plasmodium blood infection in mice, without a priori knowledge of parasite antigens, MHC restriction or epitopes. [Using this approach, the candidate has determined that Plasmodium yoelii blood stage infection results in sustained expression of multiple inhibitory receptors on responding T cells and that these cells exhibit impaired cytokine production, demonstrating that these T cells have undergone functional exhaustion during prolonged malaria. Moreover, therapeutically blocking the functional engagement of at least two inhibitor receptors with their ligands in mice with established malaria results in immediate contro of parasite replication and enhanced parasite clearance. Finally, the candidate has determined that inhibitory receptor blockade has major impacts on both parasite-specific CD4 and B cell/antibody responses during blood stage Plasmodium infection. These new results provide the necessary rationale for the proposed studies to dissect the cellular and humoral basis for enhanced parasite clearance following therapeutic inhibitory receptor blockade in mice with established clinical malaria.] The candidate has more than 10 years of experience with immunologic techniques and approaches relevant to this application. The K22 award will provide the resources necessary to advance the candidate's goal of successfully establishing an NIH R01- funded, independent laboratory to study in detail the quantitative and qualitative features of Plasmodium- specific CD4 T cell and B cell/antibody responses. Collectively, by virtue of the candidate's new approaches and methodologies, the studies detailed herein will provide critical insight into the features of anti-Plasmodial adaptive immunity that determine protection, which will impact current and future therapies and approaches to vaccine design in the context of Plasmodium infection. )